7536 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist induces apoptosis in human cancer cell lines and has shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 were enrolled at 15 European sites. Pts received T or placebo (PL) IV + carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. In the case of complete response (CR)/partial response (PR) or stable disease, T or PL was given as maintenance therapy. The dosage regimen was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS) and objective response rate (ORR) (CR + PR), safety. Efficacy was assessed in both the full population and a prospectively-defined FCGR genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR = 0.96; 95% CI: 0.6, 1.6. Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 14.5) for PL (HR = 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts (n = 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a non-significant trend towards increased PFS with T vs PL (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% with PL). The number of treatment cycles was similar in both treatment arms. Conclusions: T does not improve the efficacy of C/P as treatment for systemic therapy-naïve, unselected advanced NSCLC pts. T was well tolerated and is being investigated in other settings.